While genetic susceptibility and environment clearly represent realms of influence for the development of type 1 diabetes, a series of immunological abnormalities are inherent to the immune dysregulation that results in the autoimmune destruction of pancreatic (3 cells. Indeed, our previous PO1 studies of individuals with or at increased-risk for type 1 diabetes, as well as in the non-obese diabetic (NOD) mouse model of the disease, associated a series of specialized immune system cells and specific mediators with the disorder. However, issues related to the interplay between these specialized cells and the mediators that allow for abnormal immune regulation, the specificity of these immunological defects in type 1 diabetes versus other autoimmune and metabolic disorders, as well as the ontogeny of immune dysregulation in the natural history of the disease (both prior to and after onset) remain unclear. Our goal in seeking renewal of this P01 grant is to address these outstanding issues;all for the continued purpose of testing our hypothesis that antigen presenting cells (dendritic cells, macrophage/monocytes), through their interaction with components of the cellular immune system (iNKT cells, regulatory T cells), form a critical facet to the immune dysregulation which results in type 1 diabetes. This P01 renewal will examine this hypothesis through three separate but highly interactive Projects. The Projects utilize the NOD mouse model and an extremely valuable population of human subjects with or at increased-risk for type 1 diabetes, as well as healthy controls or persons with type 2 diabetes. The PO1 application is comprised of three Projects: Project 1 (S.B. Wilson, PI) - iNKT Cell Gene Expression and Effector Function in Type 1 Diabetes;Project 2 (M. Clare-Salzler, PI) - Interferons alpha/beta in Type 1 Diabetes Pathogenesis;and Project 3 (M. Atkinson, PI) - Immune Regulation and Type 1 Diabetes Pathogenesis. The projects will be supported by two well established Core facilities: A-Administration;B-Pathology &Immunology. The successful completion of these P01 studies should prove beneficial to improving our understanding of those events critical to the natural history of type 1 diabetes, identifying markers that enhance our ability to monitor cellular immune activities in the disease, uncovering the interplay between the genetics, environment and the immune response in the pathogenesis of type 1 diabetes, as well as developing immunotherapies capable of preventing or reversing the disorder.